REVIEW ARTICLEpublished: 09 October 2014

doi: 10.3389/fonc.2014.00277

Serum biomarkers for the detection of cardiac toxicityafter chemotherapy and radiation therapy in breastcancer patientsSiboTian1, Kim M. Hirshfield 2, Salma K. Jabbour 1, DeborahToppmeyer 2, Bruce G. Haffty 1, Atif J. Khan1 andSharad Goyal 1*1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA2 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Edited by:John Varlotto, University ofMassachusetts Medical Center, USA

Reviewed by:Dalong Pang, Georgetown UniversityHospital, USAMichael Wayne Epperly, University ofPittsburgh Cancer Institute, USA

*Correspondence:Sharad Goyal , Department ofRadiation Oncology, Rutgers CancerInstitute of New Jersey, 195 LittleAlbany Street, New Brunswick, NJ08903, USAe-mail: goyalsh@rutgers.edu

Multi-modality cancer treatments that include chemotherapy, radiation therapy, and tar-geted agents are highly effective therapies. Their use, especially in combination, is limitedby the risk of significant cardiac toxicity. The current paradigm for minimizing cardiac mor-bidity, based on serial cardiac function monitoring, is suboptimal. An alternative approachbased on biomarker testing, has emerged as a promising adjunct and a potential sub-stitute to routine echocardiography. Biomarkers, most prominently cardiac troponins andnatriuretic peptides, have been evaluated for their ability to describe the risk of potentialcardiac dysfunction in clinically asymptomatic patients. Early rises in cardiac troponin con-centrations have consistently predicted the risk and severity of significant cardiac eventsin patients treated with anthracycline-based chemotherapy. Biomarkers represent a novel,efficient, and robust clinical decision tool for the management of cancer therapy-inducedcardiotoxicity.This article aims to review the clinical evidence that supports the use of estab-lished biomarkers such as cardiac troponins and natriuretic peptides, as well as emergingdata on proposed biomarkers.

Keywords: breast cancer, cardiac biomarkers, chemotherapy, radiation therapy, cardiotoxicity

INTRODUCTIONDue to earlier detection and highly effective multi-modality treat-ments, cancer has become a largely curable disease and a chronicillness. There were an estimated 11.7 million cancer survivors in2007, a number that has grown from 3.0 million in 1970, to 9.8million in 2001 (1). The Centers for Disease Control estimatedin 2007 that 64.8% of cancer survivors had lived at least 5 yearspast their initial diagnosis, and approximately 60% of survivorswere at least 65 years old. Because of the now-chronic nature ofmalignant diseases, and the age composition of the survivors, thecardiac side effects of cancer treatments must be heeded. Cytotoxicchemotherapies such as doxorubicin, targeted therapies includingtrastuzumab, and radiotherapy have all been implicated as risk fac-tors for subsequent cardiac disease. The timing of cardiac toxicitycan vary from acutely during treatment, to chronically monthsafter treatment completion. The most clinically significant end-point is impaired left ventricular ejection fraction (LVEF) andensuing symptomatic heart failure. The current standard of detec-tion is by serial echocardiography, a resource-intensive test whoseaccuracy is operator-dependent. Biomarkers on the other hand,can be tested at closer intervals given its low-cost approach; andits accuracy is independent of operator skill. Most importantly,biomarkers have demonstrated the ability to predict cardiotox-icity before it becomes clinically apparent. The use of cardiacbiomarker in specific settings have been reviewed several times,and most recently in 2011 (2–6). However, the role of biomarkersis continually redefined by ongoing investigations. The purpose

of this review is to provide a comprehensive assessment of theevidence on cardiac troponins and natriuretic peptides as bio-markers of cardiac toxicity. Results for other proposed biomark-ers, including heart-type fatty acid-binding protein (H-FABP),glycogen phosphorylase isoenzyme BB (GPBB), C-reactive pro-tein (CRP), myeloperoxidase (MPO), and nitric oxide (NO) willalso be examined.

CARDIAC TOXICITY AFTER CANCER TREATMENTAnthracyclines (AC), either used alone, or in combination withother chemotherapy agents, are widely used agents for the treat-ment of breast cancer (7). However, their use has been limitedby significant cardiotoxicity (8). AC-induced injury has beendescribed as “type I” cardiotoxicity, a dose-dependent, progres-sive, and generally irreversible type of toxicity (9). Its mecha-nism is based on oxidative damage, mediated by reactive oxygenspecies, and leads to necrosis and apoptosis (10). Risk of devel-oping AC-induced cardiotoxicity varies between individuals, andeven low doses have led to clinical cardiac dysfunction for certainpatient subsets (11). Risk factors for developing AC-induced car-diotoxicity include cumulative dose, age, female gender, exposureto cardiotoxic agents, prior AC chemotherapy, and mediastinalradiation. The clinical manifestations of AC-associated cardiotox-icity range from left ventricular dysfunction to progressive car-diomyopathy. Doxorubicin administration is generally limited toa cumulative dose of 600 mg/m2 in patients without underlyingcardiac morbidity (12).

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The pediatric population is particularly susceptible to AC-induced cardiomyopathy; and there is likely no safe dose in chil-dren (13). The incidence of cardiotoxicity after AC treatment inchildhood is similarly dose-dependent: 11, 23, 47, and 100% suf-fered from cardiac complications after being treated with <400,400–599, 600–799, and >800 mg/m2 of AC-based chemotherapy(14, 15). Treatment with ACs has long-term implications. Sur-vivors of pediatric cancers are 8.2 times more likely to die fromcardiac causes than the general population, and 15 times morelikely to experience heart failure, with some eventually requiringheart transplants (16–18).

About 25–30% of breast cancers overexpress the cell surfacereceptor HER2. These malignancies are typically more aggres-sive, with enhanced proliferation and metastatic potential, andare associated with poor prognosis (19). Trastuzumab (Herceptin)is a monoclonal antibody that binds to the extracellular domainof the HER2 protein. Its efficacy in the adjuvant setting hasbeen investigated in numerous clinical trials. A meta-analysisdemonstrated reduction in mortality, recurrence and metastasesrates, and improved disease-free survival with trastuzumab (20).Trastuzumab, though generally well tolerated, is associated withan infrequent but clinically significant risk of long-term car-diotoxicity. Unlike AC-induced cardiac injury, trastuzumab isdescribed as “type II” cardiotoxicity. The risk of damage is dose-independent, generally reversible with discontinuation, and causesminimal ultrastructural changes (21–23). The risk of develop-ing trastuzumab-induced heart failure has been reported as 2–4% when given alone, but as high as 27% when administeredin conjunction with ACs (24, 25). With the advent of newerHER2-directed therapies, additional consideration will need tobe given to long-term cardiac side effects associated with theiruse. Clinical trials have reported fewer grade three or four car-diac toxicity with lapatinib, pertuzumab, trastuzumab emtansine(T-DM1), or neratinib in comparison to trastuzumab (26–34). Asother HER2-targeted agents are under development or evaluationfor combinatorial therapy, cardiotoxicity will remain a topic ofinterest.

Radiation therapy (RT) is major component cancer treatment;and adjuvant radiotherapy for breast cancer reduces the risk oflocal recurrences and mortality (35). However, mediastinal irradi-ation has been linked to increased cardiotoxicity, via micro- andmacrovascular damage (36, 37). A surveillance, epidemiology, andend results (SEER) analysis of 15,165 breast cancer patients foundthat of those who died more than 10 years after radiotherapy, 42%died from recurrent breast cancer, while 22% died from heart dis-ease (38). The severity of cardiac injury is related to the radiationdose absorbed by the heart, and mean heart dose is typically higherwhen RT is to employed to treat left-sided breast cancer. The SEERstudy found patients with left-sided cancers had a 44% increasedrisk of cardiac mortality. Based on several randomized studies,the relative risk for significant cardiac events ranges 1.2–3.5 afterRT (39). As RT is often combined with chemotherapy, cardiacirradiation has been described repeatedly as an additional risk fac-tor for AC-induced cardiotoxicity (40, 41). Though data are stillmaturing on the cardiac risks of radiotherapy delivered concur-rently with trastuzumab, an analysis of the NCCTG N9831 trialshowed no additional cardiotoxicity with RT (42). Advances in

radiation delivery technology, such as conformal radiation, whichlimit the amount of radiation absorbed by the myocardium, haveproven useful in reducing the burden of radiation-induced cardiacmorbidity (38, 43, 44). Regardless, prior mediastinal irradiationremains a significant cause of excessive mortality.

DETECTION OF CARDIAC DYSFUNCTIONClinically detectable cardiotoxicity is generally preceded by aninterval of subclinical cardiac dysfunction. The ability to assess therisk of potential cardiac impairment has three major implications.Risk stratification provides an opportunity to modify ongoingtreatment, alter the frequency of subsequent surveillance, and toprovide direct interventions to reduce the risk of cardiotoxicity.For these reasons, techniques for early and reliable detection ofclinically silent cardiotoxicity have been widely studied. Thoughseveral methods been explored, the optimal approach and tim-ing of monitoring cardiac function remains an area of activeinvestigation.

Serial endomyocardial biopsies, though considered the goldstandard are invasive and impractical for routine screening pur-poses (45). The most prevalent screening method is based onmeasuring LVEF before, during, and after chemotherapy withconventional 2-D transthoracic echocardiography (TTE) (46).Monitoring with multiple-gated acquisition (MUGA) radionu-clide angiography has also been recommended on the basis ofimproved accuracy (47). Because 2-D TTEs can be often limited byoperator skill, and inherently less reproducible, efforts have beendirected toward increasing its precision with refinements such as3-D echocardiography, strain and strain rate measurements, andcardiac magnetic resonance (48–51). LVEF measurements basedon cardiac imaging lack the sensitivity to detect early subclini-cal cardiotoxicity, and as a corollary, the ability to predict futuredeclines in cardiac function (52, 53). Detectable changes in LVEFusually coexist with significant functional impairment, at whichpoint the ability to regain normal cardiac function becomes lim-ited. Thus, the traditional approach for detecting subclinical signsof cardiotoxicity is suboptimal and there remains a need to effec-tively identifying patients who are at risk of developing seriouscardiac complications after chemotherapy or RT.

Over the past 15 years, serum molecules, such as cardiac tro-ponins and natriuretic peptides, have been evaluated for their roleas biomarkers of cardiac toxicity in the oncology setting. The abil-ity of these biomarkers to identify patients with potential cardiacmorbidity has been investigated in adult and pediatric popula-tions, after chemotherapy, radiation, and targeted therapies. Bio-markers represent a non-invasive, resource-efficient, and robustapproach to risk-stratify patients who have undergone cardiotoxictreatments.

CARDIAC TROPONINSCardiac troponin I (TnI) and cardiac troponin T (TnT) are twohighly sensitive and specific biomarkers of cardiac damage. Theyare two tissue-specific isoforms of proteins that constitute thecontractile apparatus in cardiac muscle. Since 2000, the Euro-pean Society of Cardiology and the American Cardiac Collegeof Cardiology have recognized cardiac troponins for their role inthe diagnosis of acute myocardial infarctions (54, 55). Cardiac

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Tian et al. Serum biomarkers of cardiac toxicity

troponins have been useful in quantifying the extent of acute car-diomyocyte injury in many other clinic settings, including heartfailure, pulmonary embolism, stroke, sepsis, and drug-inducedcardiotoxicity (56–58). Notably, because cardiac troponin con-centrations have been linked to the severity of myocyte injury andsubsequent clinical outcomes, troponins have become a tool forrisk stratification.

The validity of using cardiac troponins in detectingchemotherapy-induced cardiotoxicity was demonstrated in anearly animal study that linked TnT elevations to histologic evi-dence of cardiac damage (59). Using spontaneously hypertensiverats treated with increased higher doses of doxorubicin, TnTand Billingham cardiomyopathy scores (based on number ofmyocytes showing myofibrillar loss and cytoplasmic vacuoliza-tion) were both related to the cumulative dose of doxorubicin.Cardiac troponins have consistently demonstrated clinical value inpredicting subsequent cardiotoxicity after high-dose chemother-apy (HDC), irrespective of cancer type. This result is basedon four major experiences that enrolled approximately 200–700patients each (Table 1) (60–63). Cardiac troponins are sensi-tive and specific markers in predicting the development, andseverity of, subsequent ventricular dysfunction. The largest study,involving 703 patients (46% breast cancer) with advanced can-cers treated with HDC (62). TnI was assayed immediately and1 month after chemotherapy, while cardiac function was measuredby LVEF at baseline, and 1, 2, 6, and 12 months after complet-ing chemotherapy. Thirty percent (208) of patients demonstratedimmediate TnI elevations, and 30% of that subset showed ele-vated TnI on repeat testing at 1 month. Maximal LVEF reductionwas predicted by both persistent (r = 0.92, p < 0.001), and early(r = 0.78, p < 0.001) troponin elevations. Most importantly, TnIproved to be a biomarker with clinical implications, and not sim-ply a proxy for imaging-based measures. Forty-four percent ofpatients with persistent TnI elevations developed symptomaticheart failure, compared to 12% in the early positive group, and0.2% in the TnI negative population. Troponin positivity over0.08 ng/m2 predicted future cardiac events with a positive pre-dictive value (PPV) of 84% and negative predictive value (NPV)of 99%. TnI’s high NPV has been a recurrent theme seen inmany studies.

Left ventricular ejection fraction compromises with high-dosechemo can be evident as early as the first month, and was typ-ically followed by progressive deterioration over the next year(61). In addition, smaller studies have found substantial rela-tionships between troponin velocity during early follow-up anddecreased LVEF (83). Elevated troponins have been implicatedin predicting diastolic dysfunction via parameters such as E/Aratio in particular patient subsets treated with AC (69). Con-versely, the role for troponin in low and moderate chemother-apy doses in unclear, as evaluated in a study with 100 patientstreated with AC (median cumulative dose 226.1 mg/m2) (71).Even with TnT being assayed at five intervals from the firstdose of chemotherapy to 12 months after its completion, nopatient had recorded TnT values above the 0.1-ng/ml thresh-old. Of those who showed TnT rises after treatment, the major-ity reported normal LVEF and E/A ratio values just 1 year aftercompleting chemotherapy.

Notably, cardiac troponins have been key in facilitating the eval-uation of cardioprotective agents in two prospective randomizedtrials (68, 84). Both randomized children diagnosed with acutelymphoblastic leukemia (ALL) to doxorubicin with or withoutdexrazoxane, a free radical scavenger. In both studies, dexrazoxanedrastically reduced the incidence of above-threshold values TnTduring treatment. In the more recent experience, TnI levels dur-ing the first 90 days of treatment predicted lower LV mass and LVend-diastolic posterior wall thickness 4 years later (84).

Reports of troponin as a prognostic tool in asymptomatic sur-vivors of childhood cancers have been largely disappointing. Anearly study of children treated with doxorubicin found the mag-nitude of TnT elevation after the first dose of chemotherapy pre-dicted for the risk of subsequent echocardiographic abnormalities,including LV dilation (r = 0.8, p= 0.003), and LV wall thinning(r = 0.61, p= 0.04) 9 months later (65). The timing of injurymarkers supported the hypothesis that AC-induced injury canbegin as early as the first dose, and is driven by continuous oxida-tive stress rather than acute necrosis. However, numerous studiesdiscovered either no above-threshold troponin values, or lackedsubstantial relation with late-onset cardiac toxicity in survivors ofchildhood malignancies (67, 74, 87, 90).

In parallel with the growing usage of adjuvant trastuzumabin patients with HER2 overexpressing or amplified breast cancer,several large-scale studies have found a well-defined relation-ship between either troponin value or its interval change andtratuzumab-induced cardiac dysfunction. Cardinale et al. pro-vided the earliest evidence cardiac troponin values can stratifypatients on risk of developing trastuzumab-induced cardiotoxi-city, based on 251 breast cancer patients who were followed fora median of 14 months after completion of trastuzumab treat-ment (75). Thereafter, systolic function (LVEF) was evaluated viaechocardiography at baseline, every 3 months during trastuzumabtreatment and the first year of follow-up, and then every 6 months.Forty-two (17%) patients developed cardiac review and evaluationcommittee (CREC)-defined cardiac dysfunction; however, thosewith above-threshold TnI concentrations were at significantlyhigher risk for cardiotoxicity (62 vs. 5%, p < 0.001). Moreover, TnIpositivity was the strongest independent predictor of cardiotoxi-city (HR= 17.6, p < 0.001) and persistent LVEF impairment (HR2.33, p < 0.001). Troponin positivity predicted LVEF recovery witha PPV of 65% and NPV of 100%. This suggested that negative TnImeasurements during treatment can be used to assign a lower riskstatus to select patients who are less likely to benefit from cardiacscreening at routine intervals.

With regard to the timing of troponin rises with trastuzumabtreatment, Morris et al. found peak TnI elevations peaked occurredapproximately 2 months and four after dose-dense AC-basedchemotherapy (79). Importantly, it preceded maximum LVEFdecline by 4 months. Two studies by Sawaya et al. supported theseresults. Both examined TnI in patients who were treated with ACand trastuzumab sequentially. They first found that elevated high-sensitivity (hs)TnT measurements 3 months after chemotherapywas an independent predictor of cardiac toxicity at 6 months(81). The follow-up study combined circulating biomarkers withechocardiographic measures to refine their predictive model.Using an ultrasensitive troponin assay that established 30 pg/ml

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Table 1 | Role of cardiac troponins in the evaluation of chemotherapy and radiation-induced cardiotoxicity.

Reference Population N Treatment Tn type Cutoff Troponin evaluations Results and conclusions

Hugh-Davies

et al. (64)

Breast cancer 50 ACs and RT T 0.1 ng/ml Pre- and post-treatment No change in TnT after

45–46 Gy delivered to the

whole breast

Lipshultz et al.

(65)

ALL 15 ACs T 0.03 ng/ml Baseline, and 1–3 days after

each cycle

Correlation between TnT and

LV end-diastolic dimension

and wall thickness

Herman et al.

(59)

Animal study 37 ACs T Before, and 1 week after

chemotherapy

TnT and histological

myocardial changes in both

related to cumulative

doxorubicin dose

Cardinale et al.

(60)

Various 204 HDC I 0.5 ng/ml Before, and 0, 12, 24, 36, and

72 h after every cycle

Elevated TnI during treatment

predicted for LVEF decline

Cardinale et al.

(61)

Breast cancer 211 HDC and

RT

I 0.5 ng/ml Before, and 0, 12, 24, 36, and

72 h after every cycle

Correlation between max TnI,

number of TnI positive assays,

and max LVEF reduction

Auner et al.

(66)

Hematologic

malignancies

78 ACs T 0.03 ng/ml Within 48 h of treatment start,

then every 48 h during

treatment

Correlation between TnT

increase and median LVEF

decline

Sandri et al.

(63)

Various 179 HDC I 0.08 ng/ml Before, and 0, 12, 24, 36, and

72 h after every cycle

TnI increase predicted

subsequent LVEF decline

Cardinale et al.

(62)

Various 703 HDC I 0.08 ng/ml Before, and 0, 12, 24, 36, and

72 h after every cycle, and

1 month after treatment

Persistent TnI positivity

predicted for subsequent

LVEF decline

Kismet et al.

(67)

Pediatric solid

cancers

24 ACs T 0.01 ng/ml With imaging, >1 month after

chemo

No relationship between TnT

and echocardiographic

abnormalities

Lipshultz et al.

(68)

ALL 76 ACs T 0.01 ng/ml Throughout chemotherapy TnT persistently increased

during treatment, and

predicted for cardioprotective

response

Kilickap et al.

(69)

Various 41 ACs T 0.01 ng/ml Baseline, after first and last

cycle

Correlation between TnT

increase and diastolic

dysfunction (E/A ratio)

Perik et al. (70) Breast cancer 17 ACs and T I 0.1 g/l Before, and throughout T

therapy

No TnI elevations in 15/16

patients

Dodos et al.

(71)

Various 100 ACs T 0.1 ng/ml After first dose, last dose, and

1, 6, 12 months after last dose

No TnT elevations detected

Kozak et al.

(72)

Lung and

esophageal CA

30 ChemoRT T Baseline, 2 weeks after start

of treatment and after

TnT undetectable in 29/30

patients

Cil et al. (73) Breast cancer 33 ACs I Before and after

chemotherapy

No correlation between TnI

and LVEF decline

Mavinkurve-

Groothuis

et al. (74)

Various

pediatric

122 ACs T 0.01 ng/ml Once, with imaging No patients with elevated TnT

levels

(Continued)

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Table 1 | Continued

Reference Population N Treatment Tn type Cutoff Troponin evaluations Results and conclusions

Cardinale et al.

(75)

Breast cancer 251 ACs and T I 0.08 ng/ml Before T, every 3 months

during treatment, 1 year after

start, every 6 months

Elevated TnI values are an

independent predictor of

cardiotoxicity, and LVEF

recovery

Nellessen

et al. (76)

Lung and

breast CA

23 RT I 0.03 ng/ml Before RT, every week during

RT for 4–6 weeks

Log-transformed TnI

increased during treatment

Fallah-Rad

et al. (51)

Breast cancer 42 ACs and T T Before chemotherapy, before

T, and 3, 6, 9, and 12 months

after start of T

No change in TnT values over

time

Feola et al. (77) Breast cancer 53 ACs I 0.03 ng/ml Baseline, after 1 month, 1,

and 2 years

TnI concentrations elevated at

1 month, then returned to

normal

Goel et al. (78) Breast cancer 36 ACs and T I 0.20 ng/ml Baseline, before and 24 h

after T

No elevated TnI values

throughout

Morris et al.

(79)

Breast cancer 95 ACs and T I 0.04–

0.06 ng/ml

Every 2 weeks during

treatment, then at 6, 9, and

18 months

Elevated TnI values preceded

maximal LVEF decline, but no

relationship with max LVEF

decline

Romano et al.

(80)

Breast cancer 92 ACs I 5 or

0.08 ng/ml

(age ≤50 or

>50)

Every 2 weeks during

treatment, then at 3, 6, and

12 months

No correlation between TnI

change and subsequent LV

impairment

Sawaya et al.

(81)

Breast cancer 43 ACs and T I 0.015 ng/ml Baseline, 3 and 6 months

after chemotherapy

Elevated TnI at 3 months

predicted for cardiotoxicity

within 6 months

D’Errico et al.

(82)

Breast cancer 60 ChemoRT I 0.07 ng/ml Before, and after RT No elevated TnI

concentrations

Garrone et al.

(83)

Breast cancer 50 ACs I 0.03 ng/ml Baseline, 5, 16, and

28 months after

TnI kinetics correlated with

LVEF decline

Lipshultz et al.

(84)

ALL 156 ACs T 0.01 ng/ml Before, and daily during

induction, and after treatment

Lower incidence of

detectable TnT during

treatment with dexrazoxane

Onitilo et al.

(85)

Breast cancer 54 Taxanes

and T

I 0.1 ng/ml Baseline, and every 3 weeks

during treatment

TnI undetectable throughout

Sawaya et al.

(86)

Breast cancer 81 ACs and T I 30 pg/ml Before, every 3 months

during, and after T treatment

Elevated TnI values at end of

treatment predictive of

subsequent cardiotoxicity

Sherief et al.

(87)

Acute

leukemias

50 ACs T 0.01 ng/ml Once, with imaging No elevated TnT values

Erven et al.

(88)

Breast cancer 72 RT I 0.13 ng/ml Before and after RT Higher TnI values in L-sided

breast patients

Ky et al. (89) Breast cancer 78 ACs and T I 121.8 ng/ml Baseline, 3 and 6 months

after start of chemotherapy

Interval change in TnI

predicted cardiotoxicity

Tn, troponin; AC, anthracycline; RT, radiation therapy; HDC, high-dose chemotherapy; T, trastuzumab; LVEF, left ventricular ejection fraction; ALL, acute lymphoblastic

leukemia.

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as the cutoff concentration, they found TnI alone predicted sub-sequent cardiotoxicity with PPV of 44% and NPV of 77% (86).Adding peak systolic longitudinal strain of <19% improved thespecificity of the model, yielding a PPV of 67% and NPV of 77%.Interestingly, baseline LVEF at the time of AC completion did notpredict for future cardiotoxicity. Though the majority of stud-ies evaluating troponins in trastuzumab-induced cardiac damagehave demonstrated its usefulness, several experiences have beennegative (51, 77–79).

Despite abundant literature on radiation-induced cardiacinjury, troponins have yet to demonstrate any clinical utility. Stud-ies in which considerable numbers of patients were treated withRT as a single modality are relatively scarce. Of those that try to iso-late the effect of radiotherapy, none have been able draw clinicallyvaluable conclusions regarding the value of troponin in predict-ing radiation-induced cardiotoxicity (64, 72, 82). In fact, of fourstudies that included patients with breast, lung, and esophagealcancer, only one saw significantly elevated TnI concentrationsafter RT (88).

NATRIURETIC PEPTIDESNatriuretic peptides, such atrial natriuretic peptide (ANP), brainnatriuretic peptide (BNP), and its amino-terminal component(NT-proBNP) have been widely investigated and used in acuteand chronic heart failure for diagnosis and prognosis. In responseto increased wall stress, BNP is synthesized by ventricular car-diomyocytes as a 134-amino acid (aa) pre-pro peptide, which isthen cleaved into a 108-aa precursor molecule (proBNP). Uponrelease, proBNP is cleaved into an inactive N-terminal compo-nent (NT-proBNP) and the 32-residue active hormone BNP. Tocounteract volume overload, biological actions of BNP includenatriuresis, vasodilation, and suppression of sympathetic activ-ity (91). Chronic elevations in BNP reflect increased LV wallstress diastolic pressure, and volume overload (92, 93). More-over, NT-proBNP concentrations have been related to LVEFvalues and the severity of hearth failure (94). Thus, usingnatriuretic peptides to risk-stratify patients with potential car-diotoxicity would intuitively be an attractive strategy, as theyrepresent hemodynamic aberrancy and ventricular remodeling,and can appear prior to symptomatic heart failure and LVEFdecline (95).

A large number of studies have described significantBNP and NT-proBNP elevations with doxorubicin, epirubicin,trastuzumab, and thoracic irradiation, either alone in combi-nation therapy, though substantially fewer have found clinicalrelevant relationships (Table 2). One early study that establishedthe predictive value of NT-proBNP examined its role in patientswith various advanced malignancies treated with high-dose AC-based chemotherapy (63). Sandri et al. measured NT-proBNP atbaseline, and then at five time points within 72 h of completingeach treatment cycle. Persistent NT-proBNP measurements pre-dicted for the development of cardiac dysfunction at 12 monthswhen quantified by three LV diastolic indices. The predictivevalue of early NT-proBNP rises was also seen with a cohort ofbreast cancer patients with doxorubicin to a cumulative doseof 300 mg/m2 (80). Post-chemotherapy NT-proBNP increaseswere related to subsequent LVEF decline (r = 0.7, p≤ 0.001).

An ROC analysis using a cutoff of >36% NT-proBNP increasefrom baseline to peak predicted LV impairment at 12 monthsafter therapy with 79.2% sensitivity and specificity. Similar cor-relations between NT-proBNP elevations and LVEF values in thesetting of breast cancer treated with moderate dose epirubicinand non-Hodgkin lymphoma patients after six cycles of CHOPchemotherapy (96, 97).

Though early BNP increases have been the focus of many stud-ies for its predictive capabilities, BNP levels can remain elevated upto 2 years after AC-based treatment. This suggests that persistentneurohormonal activation, independent of acute tissue toxicity, isone underlying mechanism of late-onset AC-induced cardiotox-icity (77). BNP monitoring during chemotherapy has also beenlinked to significant diastolic dysfunction with CHOP. A studyby Nousiainen et al. revealed associations between BNP, fractionalshortening (FS) (p= 0.04), E/A ratio (p= 0.006), and trend to sig-nificance with LA diameter (p= 0.062) (99). Studies involving ACin the adult population have also seen substantial increases in NT-proBNP with no significant interactions with echocardiographicor clinical outcomes (71, 73, 98, 100).

While there has been great interest in validating natriureticpeptides as predictors of cardiotoxicity in the pediatric popula-tion, studies in this setting have seen mixed results. NT-proBNPhas been shown to be an effect indicator of cardioprotectiveinterventions (84). Specifically, children with ALL were random-ized to receive doxorubicin with or without dexrazoxane, aneffective free radical scavenger. Lipshultz et al. discovered drasti-cally reduced NT-proBNP concentrations after dexrazoxane treat-ment (47 vs. 20%, p= 0.07). Increased NT-proBNP in the first90 days of treatment also predicted abnormal LV thickness-to-dimension ratios, suggestive of late-onset LV remodeling. Ger-manakis et al. evaluated BNP nearly 4 years after AC treatmentto find an association between NT-proBNP with LV mass reduc-tions (p= 0.003) in asymptomatic survivors (103). Lastly, NT-proBNP concentrations have been consistently identified as aproxy for cumulative AC dose in survivors of childhood cancers(74, 105, 108).

The experience with natriuretic peptides corroborates large-scale studies that have shown the clinic onset of RT-induced car-diotoxicity can occur years after therapy. Significant NT-proBNPelevations have been detected as early as 9 months, and as late as6.7 years after radiation to the thorax for breast and esophagealcancer (82, 101, 106). In 64 patients with esophageal cancertreated to median dose of 60 Gy, increased NT-proBNP concen-trations were found beginning at 9 months (when compared tobaseline), and persisted at 24 months after radiotherapy. Addition-ally, NT-proBNP may be an early indicator of radiation-inducedmyocardial damage. Substantially, higher natriuretic peptide con-centrations were found in subjects with high F-fluorodeoxyglucose(FDG) accumulation on positron emission tomography (PET)corresponding to the irradiated fields (106). Similarly, NT-proBNPhas also been linked to cardiac doses in left-sided breast cancer.D’Errico et al. found significant associations between NT-proBNPand V3Gy (volume receiving at least 3 Gy), and two ratios for theheart: D15cm3/Dmean and D15cm3/D50% (where Dmean is the meandose, D50% is the median dose, and D15cm3 is the minimum isodosereceived by 15 cm3) (82).

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Table 2 | Role of natriuretic peptides in the evaluation of chemotherapy and radiation-induced cardiotoxicity.

Reference Population N Treatment BNP type Cutoff BNP evaluations Results and conclusions

Meinardi

et al. (98)

Breast

cancer

39 ACs and

RT

BNP 10 pmol/l Baseline, 1 month,

and 1 year after

chemotherapy

BNP increased as early as 1 month after

chemo; no correlation with LVEF decline

Nousiainen

et al. (99)

Non-

Hodgkin

lymphoma

28 CHOP BNP 227 pmol/l Baseline, after every

cycle, and 4 weeks

after last cycle

Correlation between BNP increases and

parameters of diastolic function (FS and

PFR)

Daugaard

et al. (100)

Various 107 ACs BNP Before, and at

various points during

treatment

BNP correlation with decreased LVEF,

but baseline and BNP change could not

predict LVEF decline

Perik et al.

(101)

Breast

cancer

54 ACs and

RT

NT-

proBNP

10 pmol/l Median 2.7 and

6.5 years after

chemotherapy

BNP increased with time and was

related to dose; cardiotoxic effects

develop over years

Sandri et al.

(102)

Various 52 HDC NT-

proBNP

153 ng/l (M

≤50), 227 ng/l

(M >50),

88 ng/l (F ≤50),

334 ng/l (F

>50)

Baseline, and 0, 12,

24, 36, and 72 h after

each cycle

Persistent NT-proBNP elevation at 72 h

predicts later systolic and diastolic

dysfunction

Germanakis

et al. (103)

Pediatric

cancers

19 ACs NT-

proBNP

0.2 pmol/ml Mean 3.9 years after

chemotherapy

Correlation between NT-proBNP and LV

mass decrease

Perik et al.

(70)

Breast

cancer

17 ACs

and T

NT-

proBNP

125 ng/l Baseline and

throughout T

treatment

Higher pre-treatment NT-proBNP values

in those who developed HF during

treatment

Aggarwal

et al. (104)

Pediatric

cancers

63 ACs BNP Once, >1 year after

treatment

completion

Higher BNP in patients with late cardiac

dysfunction by ECHO

Ekstein

et al. (105)

Pediatric

cancers

23 ACs NT-

proBNP

350 pg/ml Before and after

each AC dose

Dose-related increase in BNP from

baseline seen after first AC dose

Jingu et al.

(106)

Esophageal

cancer

197 RT BNP Before, <1 month,

1–2, 3–8, 9–24, and

>24 months after RT

Increased BNP over time and in those

with abnormal FDG accumulation

Kouloubinis

et al. (97)

Breast

cancer

40 ACs NT-

proBNP

Before and after

chemotherapy

Correlation between NT-proBNP

increase and LVEF decline

Dodos et al.

(71)

Various 100 ACs NT-

proBNP

153 or 227 ng/l

for M ≤50 or

>50; 88 or

334 ng/l for F

≤50 or >50

After first dose, last

dose, and 1, 6, and

12 months after last

dose

No significant increase in NT-proBNP

with treatment; cannot replace serial

ECHO for monitoring of AC-induced

cardiotoxicity

Kozak et al.

(72)

Lung and

esophageal

CA

30 ChemoRT NT-

proBNP

Baseline, after

2 weeks of RT, and

after RT end

No change in NT-proBNP during

treatment

Cil et al.

(73)

Breast

cancer

33 ACs NT-

proBNP

110 pg/ml Before and after

chemotherapy

Despite association, pre-chemo

NT-proBNP did not predict for later LVEF

ElGhandour

et al. (96)

Non-

Hodgkin

lymphoma

40 CHOP BNP Before first cycle and

after sixth cycle of

chemotherapy

Correlation between BNP values after

chemotherapy and LVEF

(Continued)

www.frontiersin.org October 2014 | Volume 4 | Article 277 | 7

Tian et al. Serum biomarkers of cardiac toxicity

Table 2 | Continued

Reference Population N Treatment BNP type Cutoff BNP evaluations Results and conclusions

Mavinkurve-

Groothuis

et al. (74)

Pediatric

cancers

122 ACs NT-

proBNP

10 pmol/l (M),

18 pmol/l (F),

age-adjusted

in children

(107)

Once, with imaging NT-proBNP levels related to cumulative

AC dose

Nellessen

et al. (76)

Lung and

breast CA

23 RT NT-

proBNP

100 pg/ml Before RT, every

week during RT for

4–6 weeks

Log-transformed NT-proBNP increased

during treatment

Fallah-Rad

et al. (51)

Breast

cancer

42 ACs

and T

NT-

proBNP

Before

chemotherapy,

before T, and 3, 6, 9,

and 12 months after

start of T

No change in NT-proBNP values over

time

Feola et al.

(77)

Breast

cancer

53 ACs NT-

proBNP

5 pg/ml Baseline, after

1 month, 1, and

2 years

NT-proBNP increased acutely with

treatment, and in patients with systolic

dysfunction

Goel et al.

(78)

Breast

cancer

36 ACs

and T

NT-

proBNP

110 pg/ml (age

<75),

589 pg/ml (age

>75)

Baseline, before and

24 h after T

No change in NT-proBNP with

trastuzumab

Romano

et al. (80)

Breast

cancer

92 ACs NT-

proBNP

153 pg/ml (age

≤50),

222 pg/ml (age

>50)

Every 2 weeks

during treatment,

then at 3, 6, and

12 months

Interval change in NT-proBNP predicated

for LV impairment at 3, 6, and 12 months

Sawaya

et al. (81)

Breast

cancer

43 ACs

and T

NT-

proBNP

125 pg/ml Baseline, 3 and

6 months after

chemotherapy

No relation between NT-proBNP levels

before and after treatment and LVEF

change

D’Errico

et al. (82)

Breast

cancer

60 ChemoRT NT-

proBNP

125 pg/ml Before, and after RT Correlation between NT-proBNP, V3Gy for

the heart, D15cm2 /Dmean and

D15cm3 /D50%

Lipshultz

et al. (84)

ALL 156 ACs NT-

proBNP

150 pg/ml (age

<1), 100 pg/ml

(age ≥1)

Before, and daily

during induction, and

after treatment

Correlation between NT-proBNP and

change in LV thickness-to-dimension

ratio 4 years later

Mladosievicova

et al. (108)

Childhood

leukemias

69 ACs NT-

proBNP

105 pg/ml (F),

75 pg/ml (M)

Median 11 years

after treatment

Increased NT-proBNP with exposure to

ACs

Onitilo et al.

(85)

Breast

cancer

54 Taxanes

and T

BNP 200 pg/ml Baseline, and every

3 weeks during

treatment

No correlation between elevated BNP

values and cardiotoxicity

Pongprot

et al. (90)

Pediatric

cancers

30 ACs NT-

proBNP

Age-adjusted

(109)

Once, with imaging Correlation between NT-pro BNP values

and FS and LVEF

Sawaya

et al. (86)

Breast

cancer

81 ACs

and T

NT-

proBNP

125 pg/ml Before, every

3 months during, and

after T treatment

NT-proBNP did not change with

treatment

Sherief

et al. (87)

Acute

leukemias

50 ACs NT-

proBNP

Age-adjusted

(107)

Once, with imaging NT-proBNP linked to AC dose and

abnormal tissue Doppler imaging

parameters

(Continued)

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Tian et al. Serum biomarkers of cardiac toxicity

Table 2 | Continued

Reference Population N Treatment BNP type Cutoff BNP evaluations Results and conclusions

Kittiwarawut

et al. (110)

Breast

cancer

52 ACs NT-

proBNP

45 pg/ml Baseline, and end of

fourth cycle

Correlation between NT-proBNP and FS

Ky et al.

(89)

Breast

cancer

78 ACs

and T

NT-

proBNP

Baseline, 3 and

6 months after start

of chemotherapy

No relationship between NT-proBNP

values and cardiotoxicity

BNP, brain natriuretic peptide; NT, N-terminal; AC, anthracycline; RT, radiation therapy; HDC, high-dose chemotherapy; T, trastuzumab; LVEF, left ventricular ejection

fraction; HF, heart failure; ALL, acute lymphoblastic leukemia; FS, fractional shortening; PFR, peak filling rate.

The role of NT-proBNP in predicting trastuzumab-inducedcardiac dysfunction has been evaluated in five recent stud-ies. Higher pre-treatment (immediately post-chemotherapy) NT-proBNP concentrations were found in patients with metastaticbreast cancer who developed symptomatic heart failure duringtreatment (p= 0.009) (70). The other four failed to find anymeaningful relationship between BNP or its interval changeswith measures of cardiac function; often no significant changeswere found between pre- and post-treatment NT-proBNP con-centrations (51, 78, 81, 89). Concerns regarding sufficient follow-up and superimposed AC-induce cardiotoxicity make it unclearwhether NT-proBNP has any clinical usefulness in predictingtrastuzumab-induced cardiac dysfunction.

OTHER PROPOSED MARKERSHeart-type fatty acid-binding protein and glycogen phosphory-lase isoenzyme BB have been evaluated jointly as potential bio-markers of cardiac toxicity in several studies. Both GPBB andH-FABP are considered markers of early cardiac injury. GPBBis a cardiac-specific enzyme of glycogenolysis, which providesglucose to cardiac muscle. Because GPBB is released into cir-culation 2–4 h after myocardial injury, it may be a sensitive,and early marker of acute coronary syndromes. Moreover, GPBBhas been found useful for the risk stratification in acute coro-nary syndromes, as it is an independent predictor of mortal-ity (111). Similarly, H-FABP is a low molecular weight proteinnormally found in the cytoplasm, but can be detected within2–3 h after significant myocardial injury (112, 113). In threestudies that evaluated GPBB in patients with leukemias andlymphomas, Horacek et al. found approximately 17–21.7% ofpatients with elevated GPBB concentrations after either AC-based chemotherapy or a preparative regimen for hematopoieticstem cell transplantation (114–116). Based on threshold val-ues of 7.30 µg/l for GPBB and 4.50 µg/l for H-FABP, no studyreported significant elevations in H-FABP, and only one founda correlation between GPBB elevation and LV diastolic dys-function via impaired relaxation (114). However, in a cohortof non-Hodgkin lymphoma subjects treated with doxorubicin-based chemotherapy, H-FABP measured 23 h after the first cycleof CHOP was correlated with LVEF assessed after six cycles(r =−0.836, p < 0.001) (96). Though numerous studies havefound elevated GPBB after chemotherapy, and one has relatedH-FABP with subsequent systolic dysfunction, none have yetlinked biomarker elevations with clinical outcomes in larger

populations, which leaves the clinical relevance of these twoischemic markers unclear.

C-reactive protein is an acute phase protein that is synthe-sized during an inflammatory response. Its expression is regulatedby cytokines such interleukin (IL)-1, IL-6, and tissue necrosisfactor-α (TNF-α). In the context of stable coronary artery dis-ease, myocardial infarction, and congestive heart failure, elevatedCRP is predictive of decreased LVEF and diastolic dysfunction(117–119). Using a high-sensitivity (hs) assay in breast cancerpatients, hsCRP concentrations≥3 mg/l predicted impaired LVEFwith 92.9% sensitivity and 45.7% specificity (PPV, 40.6%; NPV,94.1%). As maximum hsCRP elevations were seen on average78 days before echocardiographic detection, hsCRP may prove tobe effective in identifying patients who are less likely to benefitfrom more stringent follow-up. While Lipshultz et al. found higherCRP values in survivors of various childhood cancers, regardless ofexposure to cardiotoxic treatment with modest correlation with LVmass, wall thickness, and dimension (120), multiple studies havefound no clinical value in CRP measurements (79, 84, 89).

Myeloperoxidase is a proinflammatory enzyme that expressedby polymorphonuclear neutrophils that is indicative of oxidativestress, and involved in lipid peroxidation. It has also been iden-tified for its prognostic value in predicting future cardiovascularevents in acute coronary syndromes and adverse outcomes in heartfailure (121, 122). MPO was identified as one of two predictors ofcardiotoxicity in breast cancer patients treated with ACs and Her-ceptin, from a panel of potential biomarkers including CRP, NT-proBNP, growth differentiation factor (GDF)-15, placenta growthfactor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1,and galectin (gal)-3 (89). Ky et al. found that for patients with90th percentile MPO interval change from baseline (422.6 pmol/lincrease), the probability of CREC cardiotoxicity at 15 months was34.2%, and the risk of future cardiac toxicity was amplified witheach standard deviation increase in MPO concentration (HR 1.34,p= 0.048). When considered jointly with 90th percentile intervalTnI elevations, the risk of cardiotoxicity by 15 months was 46.5%.

Nitric oxide is a small molecule generated by NO synthasefrom l-arginine in numerous cell types, including endothelialcells, platelets, neutrophils, and macrophage (123). NO is a keyregulator of cardiomyocyte contractility, and inducible NO syn-thase has been implicated in the pathophysiology of heart failureand cardiomyopathy (124, 125). Dysregulated NO synthesis hasbeen found to be one mechanism involved in doxorubicin-inducedcardiotoxicity, as studies in bovine endothelial cells have linked

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Tian et al. Serum biomarkers of cardiac toxicity

redox activation of doxorubicin with endothelial NO synthesis indoxorubicin-induced apoptosis (126, 127). NO has been describedas a potential marker of subclinical cardiac dysfunction in the pedi-atric setting. Guler et al. found significantly higher nitrite values inchildren treated with doxorubicin compared to healthy controls,and in those with abnormal/borderline LVEF and FS values (92.35vs. 59.26 µmol/l, p= 0.038) (128).

CONCLUSION AND FUTURE DIRECTIONSCardiac toxicity associated with cancer treatment is a growingsource of significant morbidity and mortality. Current screeningpractices are suboptimal as they provided limited opportunity tointervene and change the course of disease progression. Serum bio-markers, and especially cardiac troponins in patients treated withHDC, represent an effective method for monitoring cardiac status,and identifying patients who may benefit from early medical inter-vention. There is also growing evidence for a combined approachin which biomarkers and echocardiograms are co-interpreted.

A discussion of any screening test’s validity would be incom-plete without considering Wilson and Junger’s classic screeningcriteria (129). Of the 10 criteria, some are evident, such as“the con-dition sought should be an important health problem.”And of the10, the two that deserve additional mention here are “there shouldbe an accepted treatment for patients with recognized disease,”and“there should be an agreed policy on whom to treat as patients.”Both of these questions were addressed by a large randomizedstudy that evaluated the cardioprotective effects of enalapril, anangiotensin-converting-enzyme inhibitor routinely used for con-gestive heart failure (130). Of 413 patients treated with high-doseACs in the study, 114 patients developed early increases in TnI andwere randomized to receive either enalapril (n= 56) or placebo(n= 58). In the intervention arm, enalapril was given for 1 year,starting 1 month after chemotherapy. The placebo arm sufferedfrom a significant and progressive decline in LVEF (62.4 vs. 48.3%at 12 months, p < 0.001), as well as increases in end-diastolicand end-systolic volume. Moreover, the treatment group bene-fited from a lower incidence of adverse cardiac events (2 vs. 52%,p < 0.001). Other investigators have evaluated the beta-blockersnebivolol and carvedilol in the randomized setting, finding treat-ment during AC chemotherapy offered significant protection ofLVEF in both interventions (131, 132). Though investigations arestill ongoing, the results accumulated so far suggests cardiotoxicity,if detected early enough, and treated appropriately, is a potentiallytreatable condition. Additionally, the study populations and crite-ria used for treatment have provided a foundation for managementdecisions that can further refined.

As data on the treatment of chemotherapy-induced cardiotox-icity continue to accumulate, the objective of validating and refin-ing biomarker-based screening strategies becomes more and moreclear. Because, clinically apparent signs of cardiac injury oftenoccur years after initial therapy, there are few studies that havebeen able to link early rises in biomarker concentrations with clin-ical endpoints. Thus, there is a need longer for long-term datato either confirm or refute any meaningful relationship betweenearly biomarker status and long-term cardiac morbidity. Addi-tionally, because the optimal schedule of biomarker assessmentsremains unclear, the integration of biomarker evaluations into

large prospective clinical trials is critical. As the burden of anti-neoplastic therapy-induced cardiac morbidity increases, so doesthe need to find effective strategies for risk stratification andmanagement of therapy-induced cardiotoxicity.

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Conflict of Interest Statement: The authors declare that the research was conductedin the absence of any commercial or financial relationships that could be construedas a potential conflict of interest.

Received: 30 July 2014; accepted: 23 September 2014; published online: 09 October2014.Citation: Tian S, Hirshfield KM, Jabbour SK, Toppmeyer D, Haffty BG, KhanAJ and Goyal S (2014) Serum biomarkers for the detection of cardiac toxicityafter chemotherapy and radiation therapy in breast cancer patients. Front. Oncol.4:277. doi: 10.3389/fonc.2014.00277This article was submitted to Radiation Oncology, a section of the journal Frontiers inOncology.Copyright © 2014 Tian, Hirshfield, Jabbour, Toppmeyer, Haffty, Khan and Goyal.This is an open-access article distributed under the terms of the Creative CommonsAttribution License (CC BY). The use, distribution or reproduction in other forums ispermitted, provided the original author(s) or licensor are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice. Nouse, distribution or reproduction is permitted which does not comply with these terms.

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